In order for immune cells, such as T cells, to respond to foreign proteins, two signals must be provided by antigen-presenting cells (APCs) to resting T lymphocytes (Jenkins, M. and Schwartz, R. (1987) J. Exp. Med. 165:302-319; Mueller, D. L. et al. (1990) J. Immunol. 144:3701-3709). The first signal, which confers specificity to the immune response, is transduced via the T cell receptor (TCR) following recognition of foreign antigenic peptide presented in the context of the major histocompatibility complex (MHC). The second signal, termed costimulation, induces T cells to proliferate and become functional (Lenschow et al. (1996) Annu. Rev. Immunol. 14:233). Costimulation is neither antigen-specific, nor MHC restricted and is thought to be provided by one or more distinct cell surface polypeptides expressed by APCs (Jenkins, M. K. et al. (1988) J. Immunol. 140:3324-3330; Linsley, P. S. et al. (1991) J. Exp. Med. 173:721-730; Gimmi, C. D., et al. 1991 Proc. Natl. Acad. Sci. USA 88:6575-6579; Young, J. W. et al. (1992) J. Clin. Invest. 90:229-237; Koulova, L. et al. (1991) J. Exp. Med. 173:759-762; Reiser, H. et al. (1992) Proc. Natl. Acad. Sci. USA 89:271-275; van-Seventer, G. A. et al. (1990) J. Immunol. 144:4579-4586; LaSalle, J. M. et al. (1991) J. Immunol. 147:774-80; Dustin, M. I. et al. (1989) J. Exp. Med. 169:503; Armitage, R. J. et al. (1992) Nature 357:80-82; Liu, Y. et al. (1992) J. Exp. Med. 175:437-445).
In addition to the well-known co-stimulatory pathways, co-inhibitory pathways exist to downregulate T cell activation and immune responses and modulating such co-inhibitory pathways can be used to effectively modulate immune responses. For example, bockade of co-inhibitory pathways offers an approach to stimulate immune responses by blocking negative signals and so has therapeutic potential for treating such ailments as cancer and chronic infectious diseases, such as human immunodeficiency virus (HIV) infection, hepatitis C virus (HCV) infection, malaria, and tuberculosis (TB). However, a network composed of at least (a) PD-L1 and PD-L2 interacting with PD-1; (b) PD-L1 interacting with B7-1; and (c) other receptors interacting with PD-L1 and/or PD-L2 present a complex set of co-inhibitory pathways to target. Current agents only block a subset of these interaction. Indeed, efforts to generate agents that modulate these co-inhibitory pathways have focused on single agents that specifically modulate subsets of interactions. For example, an existing PD-1 monoclonal antibody (mAb) might block the interaction between PD-1 and the PD-1 ligands, PD-L1 and PD-L2, but may not block the interaction between PD-L1 and B7-1 or PD-1 ligands and other receptors (e.g., PD-L2 and RGMb). Thus, such an anti-PD-1 mAb would block only a subset of interactions. Moreover, methods of generating such agents, such as immunization of animal models with PD-L1 or PD-L2 polypeptides, do not yield PD-L1 and PD-L2 dual binding agents since host PD-L1 and PD-L2 leads to tolerization and deletion of the B cells that would produce such agents. Also, the use of large PD-L1 and PD-L2 polypeptides for immunization purposes functionally obscures common epitopes that would give rise to antibodies capable of binding both targets. For example a wild-type mouse will delete antibodies that react against mouse PD-L1 and PD-L2 and so remove a large number of antibodies that bind to structures conserved between human and mouse PD-L1 or PD-L2.
Accordingly, there exists a need in the art to developing compositions with an enhanced ability to simultaneously modulate co-inhibitory pathways and methods of using such compositions to effectively diagnose, prognose, and provide therapy for applications where such enhanced co-inhibitory pathway modulating abilities are beneficial.